Tumor associated monoclonal antibodies (mAb's) are potential therapeutic agents as selective carriers of cytotoxic agents to malignant cells. This hypothesis is tested in animal model systems with mAbs directed toward antigens associated with a variety of malignancies. The cytocidal agents employed are various radionuclides and their relative efficacy when conjugated to targeting vectors such as monoclonal antibodies (mAb's) is assayed. The radionuclides chosen for study span the range of radionuclidic properties available thereby assaying the effects of emission energy, half-life, and type of emission. Research continues to focus on expanding practical clinical use of Y-90 and on performing pre-clinical studies with the alpha-particle emitting radionuclides Bi-212, Bi-213, Ac-225, and At-211. Ongoing clinical trials currently employ the second generation bifunctional chelating agent 1B4M-DTPA (aka MX-DTPA or Tiuxetan) for sequestering Y-90 and or the CHX-A'' DTPA for Y-90 and / Bi-213. Both are suitable for imaging with either In-111 or Y-86. Recent numerous pre-clinical results in the ongoing development of novel bifunctional chelating agents and linkers for targeted radiotherapy with the alpha-emitting radionuclides Bi-213, Ac-225, and At-211 have been completed. In the case of Bi-213, a specific potential clinical application of treating prostate cancer with an antibody that targets PSMA(ext) demonstrated significant delay in tumor onset, extended life expectancy, and decreased levels of PSA in a murine model with single doses of radioimmunoconjugate. Studies addressing the possibility of using Ac-225 as a therapeutic radionuclide in targeted radiotherapy applications using the most stable in vivo chelating agent to date, HEHA, were performed in two different murine models, a vasculature targeting model and a solid tumor model. Both studies independently indicated there to be significant unacceptable toxicity originating from the decay product daughters. While this radionuclide may still be of value in a limited setting of rapid targeting and internalization, this condition in conjunction with the challenges associated with coordination chemistry eliminate this radionuclide from clinical contention. Studies with At-211 have yielded a novel protein modification reagent wherein the linking moiety has been removed from being the traditional aryl carboxylate active ester and placed several atoms away from the aryl astatine bond. Pre-clinical studies with this novel reagent termed SAPS conjugated to humanized monoclonal antibody anti-Tac indicate this agent to be stale in vivo and equivalent to the indirectly radio-iodinated protein in every regard. In the case of both Bi-213 and At-211, pre-clinical studies continue to evaluate potential therapeutic applications that may be translated into clinical protocols. Studies with Bi-213 have also been expanded to include investigation into use of pre-targeting protocols. Preliminary results of streptavidin conjugated monoclonal antibody humanized anti-Tac in a murine T-cell leukemia model have been completed with significant therapeutic levels of efficacy being obtained with single doses of Bi-213. With the recent revival in availability of both Bi-212 and Pb-212, pre-clinical evaluation of Bi-213, Bi-212, and Pb-212 for the treatment of disseminated intraperitoneal disease such as ovarian and pancreatic cancer have been initiated. Preliminary results have indicated that substantial increases in median life expectancy in murine models are possible with single doses of these isotopes conjugated to clinically relevant antibodies such as CC49 or Herceptin.